The goal of the proposed project is to determine mechanisms regulating synaptic effectiveness and synaptic plasticity at neuromuscular junctions, using a combined physiological and morphological approach. Synaptic effectiveness will be assessed by estimating the safety margin for neuromuscular transmission and by using intracellular recording and voltage clamping to quantify neurotransmitter release and muscle fiber electrical properties. Light microscopy will be used to search for morphological correlates of synaptic effectiveness at single identified endplates whose release properties have been analyzed. Freeze fracture electron microscopy will be used to correlate average synaptic effectiveness with presynaptic intramembranous ultrastructure. The following naturally occurring and experimentally induced forms of plasticity will be examined: 1) differences in transmitter release between nerve terminals of the same size in different muscles; 2) the dependence of spontaneous and evoked release upon muscle stretch; 3) the increase in release seen in one muscle when its contralateral homologue is denervated; and 4) changes in release that depend on the size of a motoneuron's peripheral field. This project should advance our understanding of how peripheral synapses are regulated and what role these regulatory processes play in normal neuromuscular function and disease-related changes. The major significance of this study, however, may lie in its contribution to understanding comparable synaptic plasticity in the central nervous system. Such plasticity seems to play an important role in the development and maintenance of the brain and its repair following injury.